Summary
Background
Primary systemic amyloidosis is a severe plasma cell disorder characterized by the extracellular deposition of amyloid fibrils in different organs. Echocardiography is usually performed to assess cardiac involvement. We hypothesized that in patients with systemic amyloidosis, simple echocardiographic measurement of the left atrial (LA) diameter indexed to the body surface area might provide an important risk marker for this disease.
Methods
Between 1997 and 2011, 134 patients were diagnosed with primary systemic amyloidosis and had echocardiography within 28 days; we collected their baseline characteristics and biological and echocardiographic data retrospectively. LA enlargement was defined as recommended as M-mode LA diameter greater or equal to 23 mm/m 2 .
Results
One hundred and eleven patients (83%) had echocardiographic LA dimension data available (mean age 63 ± 11 years; 61% men; 31% previously diagnosed with systemic hypertension). Mean left ventricular ejection fraction (LVEF) and interventricular septum thickness (IVST) were 62 ± 12% and 14 ± 4 mm, respectively. Mean follow-up was 2.8 ± 2.9 years (maximum 12 years). Patients with LA enlargement had a slightly lower LVEF ( P = 0.08) and a significantly greater IVST ( P < 0.0001). Overall, 5-year survival was 57 ± 5%. However, 1-year and 5-year survival rates were markedly reduced in patients with LA enlargement versus those without LA enlargement (61 ± 7% and 39 ± 8% vs 83 ± 5% and 72 ± 7%, respectively; P = 0.0007). On multivariable analysis, after adjusting for age, sex, LVEF, IVST, presence of hypertension and creatinine concentration, LA enlargement remained an independent predictor of overall mortality at 5 years (hazard ratio 2.47; 95% confidence interval 1.11–5.90; P = 0.02).
Conclusion
LA enlargement, a surrogate marker of diastolic dysfunction, is an independent predictor of long-term mortality and may therefore help to enhance risk stratification and management of patients presenting with amyloidosis.
Résumé
Contexte
L’amylose systémique à chaînes légères (AL) est une maladie grave caractérisée par des dépôts de fibrilles amyloïdes dans différents organes. L’échocardiographie transthoracique est l’examen le plus couramment réalisé pour évaluer l’atteinte cardiaque. Nous avons émis l’hypothèse que chez des patients présentant cette maladie, une simple mesure du diamètre de l’oreillette gauche par échocardiographie peut être un important marqueur pronostique.
Méthodes
Nous avons comparé les données au diagnostic de 134 patients pris en charge pour une amylose AL systémique entre 1997 et 2011 dans notre centre. Cent onze patients (83 %) parmi eux avaient une échographie cardiaque dans les 28 jours suivant le diagnostic. La dilatation de l’oreillette gauche a été définie tel que recommandé, par un diamètre supérieur ou égal à 23 mm/m 2 . Les données démographiques, biologiques et échographiques ont été collectées de façon rétrospective.
Résultats
Dans la population d’étude de 111 patients, l’âge moyen est 63 ± 11 ans ; 61 % sont de sexe masculin et 31 % ont des antécédents d’hypertension artérielle. Le temps de suivi moyen était de 2,8 ans (max 12 ans). Les patients avec oreillette gauche dilatée supérieure ou égale à 23 mm/m 2 avaient une fraction d’éjection plus basse et un septum interventriculaire significativement plus épaissi. La survie globale à cinq ans était de 57 ± 5 %. Toutefois, ce taux de survie à un et cinq ans était significativement diminué chez les patients avec une oreillette dilatée : 61 ± 7 % et 39 ± 8 % contre 83 ± 5 % et 72 ± 7 % respectivement chez ceux dont l’oreillette n’est pas dilatée ( p = 0,0007). En analyse multivariée, après ajustement pour l’âge, le sexe, la fraction d’éjection ventriculaire gauche, la présence d’hypertension, l’épaisseur du septum et la créatinémie, la dilatation de l’oreillette gauche reste un facteur indépendant prédictif de mortalité globale à cinq ans (HR 2,47 ; 95 % CI 1,11–5,90 ; p = 0,02).
Conclusion
La dilatation de l’oreillette gauche, est un marqueur indépendant de mortalité à long terme, qui peut contribuer à améliorer la stratification du risque et la prise en charge des patients présentant une amylose AL primitive.
Background
Primary systemic amyloidosis is a severe plasma cell disorder characterized by the deposition of amyloid fibrils in different organs. This process damages the involved organs and impairs their function. Myocardial involvement is not unusual in patients with primary systemic amyloidosis and results in progressive heart failure; thus, it has a major impact on prognosis. Without specific treatment, median survival is less than 6 months for symptomatic patients . TTE is the most common test performed to diagnose cardiac involvement. When cardiac involvement is suspected, TTE may show typically: hypertrophied LV walls, left atrial enlargement, LV diastolic dysfunction and, at a later stage, severe restrictive cardiac pattern. The LA is an important feature of diastolic dysfunction and the degree of LA enlargement is directly related to the impairment of LV dysfunction in different cardiac diseases where diastolic dysfunction is predominant.
In the last few years, it has been shown that LA size, as measured by TTE, confers independent prognostic information regarding cardiovascular events and mortality after consideration of various known clinical and echocardiographic predictors .
The LA diameter, as measured by TTE, is a valid surrogate of LA size although less precise than the calculated LA volume . It is more easily obtainable, reproducible and less time consuming to measure than LA volume; in fact, measurement of the LA diameter has, for a long time, been a part of the standard echocardiographic evaluation and in previous studies it has been correlated with outcome and prognosis in other heart diseases . Accordingly, we sought to determine whether this very simple measurement might provide important prognostic information in patients with primary systemic amyloidosis.
The purpose of this study was to determine the prognostic value of LA size in patients with primary systemic amyloidosis.
Methods
Patient population
The study included 134 patients with confirmed primary systemic amyloidosis who were admitted to the CHU Limoges haematology department between June 1997 and April 2011. The diagnosis was confirmed by an organ biopsy that demonstrated typical Congo red birefringence under polarized light, further confirmed by the presence of monoclonal proteins in the serum and/or a monoclonal population of plasma cells in the bone marrow .
Patients with localized amyloidosis or a history of familial or senile amyloidosis were excluded from our study. Affected organs were determined based on standard criteria for the evaluation of systemic amyloidosis .
In our study population, 67 patients (60%) with primary systemic amyloidosis were considered to have cardiac involvement on the basis of clinical history, typical electrocardiographic features of cardiac amyloidosis and echocardiographic signs, which were: LV wall thickness greater than 12 mm (in the absence of other causes of LV hypertrophy), diastolic dysfunction, dilated LA, pericardial effusion and/or thickened free right ventricular wall.
Patients were mainly treated with conventional chemotherapy, usually the M-Dex regimen (melphalan and dexamethasone), or with new drugs (thalidomide, bortezomib and lenalidomide) for non-responders after 2005.
Data collection
We performed a retrospective collection of demographic, clinical, biological and TTE data using patients’ charts. Survival data were obtained from death certificates, family physician questionnaires or hospital records. To avoid misclassification of the cause of death, all-cause mortality was selected as the endpoint. Ninety-eight percent of patients had their follow-up completed by April 2011. LA diameter data were available for 111/134 (83%) patients included in the study. Doppler-echocardiographic measurements included assessment of LV systolic and diastolic function, LV end-diastolic diameter and LV end-systolic diameter, and LVEF was calculated using the Teicholz and/or Simpson method according to American Society of Echocardiography and European Association of echocardiography recommendations . LA anteroposterior diameter was measured by M-mode TTE in parasternal long-axis view and was indexed to body surface area (LADi). The cutoff of greater or equal to 23 mm/m 2 for LADi was used to define LA enlargement as suggested in the recommendations of the European Association of echocardiography .
Statistical analysis
Patients were divided into two groups according to LA size. Patients with LADi greater or equal to 23 mm/m 2 were considered to have LA enlargement, whereas those with LADi less than 23 mm/m 2 were considered to have a normal-sized LA. Continuous data were expressed as mean ± standard deviation and were compared by Student’s t test, using commercially available software (JMP 7-1). Categorical data were given as percentages and were compared using the Chi 2 test. A P value less than 0.05 was considered as statistically significant.
The primary endpoint was overall survival calculated from the time of first diagnosis of amyloidosis until the date of last available follow-up. The cumulative probability of an event for the survival endpoint was estimated by the Kaplan-Meier method and results are presented at 1 and 5 years. Log-rank tests were used to test for significance in survival between the two groups. We first performed a univariate Cox proportional hazard analysis to test the association between survival and the most clinically relevant variables, as well as some echocardiographic variables that were available in our dataset and are known to affect survival rate in this population. We then performed a multivariable analysis that included age, sex, presence of hypertension and the variables that were significant in the univariate analysis. Results were reported as hazard ratios with the corresponding confidence interval of probability values.
Results
The study population consisted of 111/134 patients who were referred to the CHU Limoges haematology department with echocardiographic data available at baseline. Fifty-three (54%) of the 111 patients had LA enlargement (LADi ≥ 23 mm/m 2 ).
Baseline characteristics of the total population
Among the 111 patients, 61% were men, the mean age was 63 ± 11 years, 31% had a history of hypertension and 10% had atrial fibrillation or a documented history of paroxysmal atrial fibrillation at baseline. Sixty-one percent of the patients had renal involvement based on standard criteria for the evaluation of affected organs . Similarly, cardiac involvement, as defined above, was found in 60% of patients. Mean LVEF was 62 ± 12%; mean IVST was 14 ± 4 mm. Other baseline characteristics are shown in Table 1 . It should be noted that E/E’ ratio obtained at the lateral side of the mitral annulus was available only in 65% of the study population and the mean E/E’lat was 15 ± 7.
| Clinical data | All ( n = 111) | Without LA enlargement ( n = 58) | With LA enlargement ( n = 53) | P a |
|---|---|---|---|---|
| Age (years) | 63 ± 11 | 59 ± 11 | 66 ± 11 | 0.0002 |
| Men | 61 | 60 | 60 | 0.99 |
| Body surface area (m 2 ) | 1.79 ± 0.19 | 1.79 ± 0.2 | 1.79 ± 0.18 | 0.94 |
| Organ involvement > 2 | 76 | 69 | 83 | 0.08 |
| Renal involvement | 61 | 59 | 62 | 0.69 |
| Cardiac involvement | 60 | 47 | 75 | 0.001 |
| 24-hour proteinuria (g/24 hours) | 3.8 ± 5.2 | 4.8 ± 6 | 2.8 ± 3.6 | 0.06 |
| Δ FLC (mg/L) | 566 ± 972 | 589 ± 1210 | 563 ± 655 | 0.89 |
| Creatinine level (μmol/L) | 139 ± 152 | 111 ± 113 | 167 ± 182 | 0.08 |
| Hypertension | 31 | 23 | 38 | 0.1 |
| CAD | 4 | 2 | 6 | 0.3 |
| Atrial fibrillation | 10 | 4 | 16 | 0.03 |
| Microvoltage | 30 | 26 | 34 | 0.4 |
| LVEDD (mm) | 43 ± 6 | 44 ± 7 | 43 ± 6 | 0.2 |
| LVESD (mm) | 28 ± 5 | 28 ± 5 | 28 ± 5 | 0.8 |
| IVST (mm) | 14 ± 4 | 13 ± 3 | 15 ± 4 | < 0.0001 |
| IVST > 12 mm | 55 | 40 | 74 | < 0.0004 |
| LVEF (%) | 62 ± 12 | 64 ± 11 | 60 ± 13 | 0.08 |
| LVEF < 50% | 17 | 13 | 24 | 0.01 |
| E/A | 1.98 ± 4.2 | 1.19 ± 0.8 | 2.79 ± 5.6 | 0.08 |
| DT (ms) | 214 ± 89 | 228 ± 84 | 201 ± 94 | 0.2 |
| E/E’lat | 15 ± 7 | 12 ± 7 | 17 ± 8 | 0.02 |
| E/E’lat > 13 | 51 | 38 | 58 | 0.05 |
| LAD (mm) | 40 ± 8 | 35 ± 5 | 45 ± 6 | < 0.0001 |
| LADi (mm/m 2 ) | 22.6 ± 4 | 20 ± 2 | 26 ± 3 | < 0.0001 |
| Death | 43 | 33 | 55 | 0.01 |
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